Field of the Invention
The present invention relates generally to the fields of pharmacy, cell biology, and molecular biology, more particularly to an agonist peptide that acts on the adiponectin receptor for the treatment of type 2 diabetes.
Description of the Related Art
Diabetes is a serious metabolic disease with hyperglycemia. It is caused by defects in insulin secretion or abnormal function of insulin, such as insulin secretion reduction, resistance to insulin, etc., due to genetic or environmental factors, as a result of which glucose in blood is not transferred to or stored in cells and remains in an excessively large amount in blood, resulting in hyperglycemia, in which the blood glucose level is much higher than that of normal people. Diabetes is largely classified into type 1 diabetes (T1), type 2 diabetes and gestational diabetes.
In particular, type 2 diabetes, to which the present invention relates, accounts for most of the diabetes occurring in the Republic of Korea. Unlike type 1 diabetes, which occurs mostly in children, type 2 diabetes occurs mainly in adults. It occurs because of an insufficient amount of insulin secretion in vivo or resistance to insulin due to cells which do not respond to insulin.
Diabetes symptoms can be controlled through weight loss, healthy diet, sufficient exercise, and continuous monitoring of blood sugar level. However, although this disease can be controlled in the early stages with drugs, it gradually worsens and eventually requires insulin injections due to its progressive nature. Overweight and obese people are known to have a much higher risk of developing type 2 diabetes than normal weight people because they secrete chemicals that can destabilize the cardiovascular/metabolic system. It can be said that the risk of developing type 2 diabetes increases with age, but this can be considered to a result of an increase in body weight and a decrease in physical exercise.
The existing antidiabetics are largely classified into insulin preparations, sulphonylurea-based drugs, thiazolidinedione (TZD)-based drugs, biguanide-based drugs, α-glucosidase inhibitors, meglitinide-based drugs, incretin mimetics, DPP-IV inhibitors, etc. If, after diagnosis of diabetes, dietary and exercise therapies fail, the diabetes is usually treated with a single or combination therapy of antidiabetics, with reference to the guidelines of the American Diabetes Association (ADA). Here, the primary drug is metformin, which is a biguanide-based drug, and the secondary and tertiary drugs are sulfonylurea-based drugs, glinide-based drugs, thiazolidinedione-based drugs, DPP4 inhibitors, etc. Thereafter, GLP-1 (glucagon like peptide-1) agonist injections or insulin injections are used.
Phenformin and metformin, which belong to biguanides, have been used as antidiabetics since 1957. However, since phenformin produced side effects of lactic acidosis, it has been banned in many countries. Currently, metformin is the most commonly used type 2 antidiabetic in the world. Metformin lowers the blood sugar level without causing hypoglycemia or facilitating insulin secretion. Further, metformin does not influence, or slightly reduces, body weight and has beneficial effects on plasma lipids. The major side effect of metformin therapy occurs in digestive organs. Patients taking 2,550 mg of metformin per day experience abdominal discomfort, abdominal inflation, metallic taste, etc.
TZD-based drugs derived from clofibrate, which is a hyperlipidemia treatment with some hypoglycemic effect, are antidiabetics which have a hypoglycemic effect and some hyperlipidemia treatment effect. TZDs reduce resistance to insulin and boost insulin-induced blood sugar consumption, as well as control the blood sugar level by increasing the glucose consumption rate in muscle and fat and suppressing blood sugar production in the liver. TZDs are a ligand of PPARγ, a gene that generally regulates genes involved in lipocyte differentiation and lipoprotein metabolism. Activation of PPARγ by TZDs results in lipocyte differentiation, improved glucose consumption in lipocytes and improved resistance to insulin. It is known that since PPARγ is expressed in a very small amount in muscle cells and is not expressed in hepatocytes, the improved resistance to insulin by TZD in muscle is due to an indirect effect resulting from its action in lipocytes. The main side effects of TZD-based drugs are weight gain, edema, etc.
α-Glucosidase inhibitors (AGIs) are drugs that are not absorbed. They are not drugs that improve the pathological defects of type 2 diabetes. α-Glucosidase is an enzyme present in the brush border of the small intestine. It breaks down carbohydrates such as starch, dextrin, and maltose into absorbable monosaccharides. Inhibitors of the enzyme do not prevent but delay the absorption of digested carbohydrates, inhibiting the sharp increase of postprandial blood sugar and insulin concentrations. In type 2 diabetic patients, adequate amounts of insulin are not secreted or insulin is secreted slowly, in response to the elevated blood sugar level following ingestion of food. Delay of the absorption of glucose in the small intestine allows the pancreas to secrete adequate amounts of insulin, thus preventing a rapid rise in postprandial blood sugar level. The rapid rise in postprandial blood sugar level is closely related to cardiovascular mortality rate. Side effects of AGIs mostly occur in the digestive system, which include abdominal pain, farts, and diarrhea. These side effects result from fluid retraction caused by an osmotic pressure generated when unabsorbed carbohydrates pass through the large intestine. The farts result from the gaseous products produced by the metabolism of carbohydrates by GI flora.
The existing oral antidiabetics currently used in clinical practice cause various side effects such as hypoglycemia, diarrhea, abdominal inflation, weight gain, lactic acidosis, cardiotoxicity and hepatotoxicity on long-term use, as well as the positive effects of sustained normalization of blood sugar. Moreover, these drugs irreversibly damage/destroy the beta cells of the pancreas, which secrete insulin, and cause resistance to insulin, leading to reduced efficacy, and eventually the patient requires insulin injections. In addition, insulin, which is the most commonly used antidiabetic, causes patient inconvenience/intolerance because it needs to be subcutaneously injected 2-3 times per day, and also has a great possibility of causing hypoglycemia. Therefore, it is necessary to develop a more effective and safe drug that can effectively reduce the blood sugar level without causing hypoglycemia as well as overcome the weight gain and resistance to insulin while protecting the pancreatic beta cells even on long-term use. Also, it is urgently required to develop a long-lasting antidiabetic for the patient's convenience.